CN110204560A - 1,2,3- thiadiazole drug molecule with tyrosine-kinase enzyme inhibition activity and its preparation method and application - Google Patents
1,2,3- thiadiazole drug molecule with tyrosine-kinase enzyme inhibition activity and its preparation method and application Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The invention discloses a kind of 1 with tyrosine-kinase enzyme inhibition activity, 2,3- thiadiazole drug molecules and its preparation method and application belong to the synthesis technical field of inhibitor class drug.Technical solution of the present invention main points are as follows: the 1,2,3- thiadiazole drug molecule has structureThe invention also discloses one kind 1, 2, the preparation method of 3- thiadiazole drug molecule, 4- methoxybenzene acetaldehyde and hydrazine hydrate and dimethyl carbonate obtain 4- methoxybenzene ethylidene methyl hydrazinocarboxylate through condensation reaction first, 4- methoxyphenyl -1 is obtained with sulphur reagent cyclization again, 2-3- thiadiazoles, 4- methoxyphenyl -1, 2-3- thiadiazoles reacts to obtain 4- (4- methoxyphenyl) -5- chlroacetone base -1 with 3- chlorpromazine chloride after organolithium reagent pulls out hydrogen, 2-3- thiadiazoles, finally with 3, 4- dimethoxyaniline obtains target compound by the nucleophilic addition of imines under the action of catalyst after substitution reaction occurs, reaction process is easy to operate and reproducible, ideal compound has certain inhibiting effect to tyrosine kinase EGFE.
Description
Technical field
The invention belongs to inhibitor class technical field of medicine synthesis, and in particular to one kind has tyrosine-kinase enzyme inhibition activity
1,2,3- thiadiazole drug molecule and its preparation method and application.
Background technique
Heterocyclic compound quantity is especially more, is widely distributed in nature, rises during development, growth of biology etc.
Great effect.At 19th-century initial stage, the acquisition of heterocyclic compound is mostly the extraction of natural products, but thus obtained chemical combination
Produce amount is very low, and purity is not high, and expensive;With the development of organic synthesis technology, in order to make full use of heterocyclic
Object is closed, chemist starts to have carried out extensive artificial synthesized heterocycle compound, and it is widely used it, wherein
Including biological medicine, energy storage material, biomimetic material, high-performance dyestuff etc..Wherein nitrogen-containing heterocycle compound is as important
Heterocyclic compound, since it has wide spectrum biological activity and pharmacological activity, such as nitrogen-containing heterocycle with unique structure
There is class compound bioactivity, the lead compound skeletons that can be used as many drugs such as sterilization, antiviral and antitumor to exist,
There is important role in medical initiative field.
In decades, heterocyclic compound such as pyrimidine, pyrroles, thiazole and imidazoles etc. and its derivative are because of biology with higher
Activity, and it is widely used in the fields such as medicine, agricultural and material, gradually cause the concern of chemists.Thiadiazoles is numerous
Important a member in azole heterocyclic compound has more biology and pharmacological activity.Thiadiazoles is containing N, S heteroatomic five
Membered heterocyclic compound, thiadiazoles and its derivative are widely used in biology, medicine and other fields at present, especially in antibacterial, antitumor, anti-
The research of cancer etc. has obtained important breakthrough;Such as 1,3,4- thiadiazole derivative is five yuan containing nitrogen and sulfur heteroatom
Compound has the extensive bioactivity such as sterilization, desinsection, anticancer, weeding, antiviral;In addition, 1,3,4- thiadiazole spreads out
Biology also has treating tuberculosis, anticonvulsion, plant growth regulating isoreactivity, can be used as the medicine of anodyne, resistant to infection medicine, Inhibiting proliferation
Object etc..1,3,4- thiadiazole compound is also widely used in terms of pesticide, for example, preventing and treating rice in fungicide from leaf blight
MBAMT;In herbicide, as fourth sulphur imidazolone, the Fluthiamidep of Bayer AG's research and development, Novartis Co., Ltd develop
Fluthiacetmethy, especially the latter, the amount of application of 4~15g/ha of Miao Hou can fully control the broad-leaved in corn and potato
Weeds;As for preventing and treating several thiazoles of sanitary insect pest in terms of insecticide, under 2.5ppm concentration, 100% kills subtropical zone in 7d
The larva of mythimna separata.2009, the designs such as Xiao synthesized 2- amino -5- (2,4- dichlorophenoxy) methyl-1,3,4- thiadiazoles
Amides compound, bacteriostatic activity test show: partial target compound has certain bacteriostatic activity, wherein 1,2 pair of compound
The inhibiting rate of wheat blacking germ is respectively 88%, 71%;3,4 pairs of anthrax-bacilus inhibiting rates of compound are respectively 68.70%,
66.94%.
Equally, 1,2,3- thiadiazoles are also a kind of thiadiazole compound important, with extensive bioactivity, due to
S atom is directly connected with N atom in its chemical structure, and chemical preparation process stability is poor, and synthesis technology is relatively difficult, at present
Research report about 1,2,3- thiadiazole compound is fewer, but due to the particularity of 1,2,3- thiadiazoles structure and
Superior bioactivity study to it significant.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of 1,2,3- thiadiazoles with tyrosine-kinase enzyme inhibition activity
Class drug molecule and its preparation method and application
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of with tyrosine-kinase enzyme inhibition activity
The structure of 1,2,3- thiadiazole drug molecule are as follows:
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of with tyrosine-kinase enzyme inhibition activity
The preparation method of 1,2,3- thiadiazole drug molecule, it is characterised in that specifically includes the following steps:
(1) 4- methoxybenzene acetaldehyde obtains 4- methoxybenzene ethylidene hydrazine through condensation reaction with hydrazine hydrate and dimethyl carbonate
Base methyl formate;
(2) 4- methoxybenzene ethylidene methyl hydrazinocarboxylate and sulphur reagent generation annulation obtain 4- methoxyphenyl-
1,2-3- thiadiazoles;
(3) 4- methoxyphenyl -1,2-3- thiadiazoles reacts to obtain 4- after organolithium reagent pulls out hydrogen with 3- chlorpromazine chloride
(4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles;
(4) 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles replaces with 3,4- dimethoxyaniline
Nucleophilic addition after reaction under the action of catalyst by imines obtains target compound.
Step (1) are as follows: in the more mouthfuls of reaction flasks with water segregator, the hydrazine hydrate and carbon that are 80% a certain amount of content
Toluene is added in dimethyl phthalate, is to slowly warm up to flow back after mixing evenly, separates what reaction system had and generated by water segregator
Moisture is cooled to room temperature by there is not moisture in water segregator during observation back flow reaction, one is added into reaction system
Then under nitrogen protection quantitative alkali compounds and 4- methoxybenzene acetaldehyde is continuously heating to flow back, by water segregator and
When remove the moisture that generates in reaction process, filtering reacting liquid, filtrate are poured into ice water while hot after reaction, pass through glacial acetic acid
Adjusting reaction solution pH is 7~8, and it is multiple to be then extracted with ethyl acetate reaction solution, is merged dry through anhydrous magnesium sulfate after organic phase
After be concentrated to get 4- methoxybenzene ethylidene methyl hydrazinocarboxylate;The 4- methoxybenzene acetaldehyde and hydrazine hydrate and carbonic acid diformazan
The inventory molar ratio of ester is 1:2:1~1.2;The alkali compounds is anhydrous barium hydroxide, sodium hydroxide or sodium methoxide;
The inventory molar ratio of the 4- methoxybenzene acetaldehyde and alkali compounds is 1:0.5~1;
Step (2) is using one of following two method:
A, in more mouthfuls of reaction flasks, a certain amount of 4- methoxybenzene ethylidene methyl hydrazinocarboxylate and 1,8- diaza two
11 carbon -7- alkene of ring and elemental sulfur adding into dichloromethane, after mixing evenly, under certain reaction temperature and nitrogen protection
Under, thionyl chloride is added dropwise to reaction solution, after dripping, is slowly increased to room temperature, is stirred to react a period of time at room temperature, leads to
Flowing nitrogen discharge reaction system gas generated is crossed, controls reaction temperature in room temperature, after reaction to reaction solution
In pour into ice water, separate organic phase after mixing evenly, water tank is extracted with dichloromethane repeatedly again, merges organic phase, then through anhydrous
Concentration is through the isolated 4- methoxyphenyl -1,2-3- thiadiazoles of silica gel column chromatography after magnesium sulfate is dry;The reaction temperature
It is 0 DEG C;The 4- methoxybenzene ethylidene methyl hydrazinocarboxylate and 11 carbon -7- alkene of 1,8- diazabicylo and elemental sulfur
Inventory molar ratio with thionyl chloride is 1:1~1.1:2~2.1:2~2.1
B, in closed reactors, Salicylaldoxime and organic acid are added in dimethyl sulfoxide, after mixing evenly,
4- methoxybenzene ethylidene methyl hydrazinocarboxylate and potassium thiosulfate are added, the air in reactor is removed in vacuum, is passed through oxygen
Gas makes the pressure in reactor reach certain numerical value and is heated slowly to certain temperature again, is slowly dropped to room temperature after reaction, subtracts
The repoussage organic acid complete except unreacted, a certain amount of water is then added into reaction solution, reaction solution is then extracted with ethyl acetate
Repeatedly, merge organic phase, then wash organic phase with sodium chloride solution, through the isolated 4- methoxybenzene of silica gel column chromatography after concentration
Base -1,2-3- thiadiazoles;The 4- methoxybenzene ethylidene methyl hydrazinocarboxylate and Salicylaldoxime and potassium thiosulfate
Inventory molar ratio is 1:0.5:1;The organic acid is formic acid or acetic acid;The reaction pressure is 0.1~0.2MPa;Institute
The reaction temperature stated is 100~120 DEG C.
Step (3) are as follows: in more mouthfuls of reaction flasks, under the conditions of -40 DEG C, under nitrogen protection, a certain amount of 4- methoxyl group
Phenyl -1,2-3- thiadiazoles is added in anhydrous tetrahydro furan, is slowly added dropwise into reaction solution dissolved with a certain amount of after stirring evenly
The tetrahydrofuran solution of organolithium reagent stirs a period of time under the conditions of -40 DEG C, is being warming up to -20 DEG C of stirrings after dripping
The tetrahydrofuran solution dissolved with 3- chlorpromazine chloride was added under the conditions of the temperature, is warming up to 0 after dripping reaction a period of time
DEG C, continue stirring a period of time, water quenching reaction is then added into reaction solution, methylene chloride is added into reaction solution, stirs
Organic phase is separated after uniformly, who wants after being neutrality with dilute hydrochloric acid adjusting pH, then is extracted with dichloromethane repeatedly, merge organic phase,
4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles is concentrated to get after being dried with anhydrous magnesium sulfate;Described is organic
Lithium reagent is lithium methide or n-BuLi;4- methoxyphenyl -1,2-3- the thiadiazoles and organolithium reagent and 3- chlorine third
The inventory molar ratio of acyl chlorides is 1:1.5:1.
Step (4) are as follows: a certain amount of 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles and 3,4- bis-
Aminoanisole and triethylamine are added in methylene chloride, are heated to 70 DEG C after mixing evenly at room temperature and are stirred to react one section
Time separates organic phase then to filtering reacting liquid, and water phase is extracted with dichloromethane repeatedly, merges organic phase, then through anhydrous sulphur
It is added in methylene chloride and Isosorbide-5-Nitrae-dioxane mixed solution, adds after mixing evenly a certain amount of after being concentrated after sour magnesium is dry
Catalyst and catalysis adjuvant, reaction temperature rises to 80 DEG C, is cooled to room temperature after reaction, water is added into reaction solution,
Then methylene chloride and Isosorbide-5-Nitrae-dioxane is evaporated off in filtering reacting liquid under vacuum conditions, then is extracted with dichloromethane anti-
It answers liquid multiple, merges organic phase, through the isolated target compound of silica gel column chromatography after being concentrated after anhydrous magnesium sulfate is dry;Institute
The inventory mole of 4- (4- the methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles and catalyst and catalysis adjuvant stated
Than for 1:0.1:0.2;4- (4- the methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles and 3,4- dimethoxy benzene
The inventory molar ratio of amine and triethylamine is 1:1:1;The catalyst is copper trifluoromethanesulfcomposite, and six perchloric acid hydrate nickel are high
Magron or six perchloric acid hydrate zinc;The catalysis adjuvant is copper carbonate.
The invention has the benefit that the present invention has synthesized a kind of 1,2,3- thiadiazoles of structure novel by new method
Class drug molecule, and tested by anti-tumor activity test and tyrosine-kinase enzyme inhibition activity, find target compound to liver
Cancer SMMC7721 cell has certain inhibiting effect, and has certain inhibiting effect to wildness EGFR kinases.
Detailed description of the invention
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of target compound.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
In the more mouthfuls of reaction flasks with water segregator, the hydrazine hydrate 13g and dimethyl carbonate 9g that content is 80% are added
Toluene 200mL is to slowly warm up to flow back after mixing evenly, separates the moisture that reaction system has and generates by water segregator, leads to
Observation about back flow reaction 3h is crossed, moisture is not occurring in water segregator, is being cooled to room temperature, anhydrous hydrogen-oxygen is added into reaction system
Change barium 9.5g and 4- methoxybenzene acetaldehyde 15g then under nitrogen protection to be continuously heating to flow back, be removed in time by water segregator
The moisture generated during dereaction, about back flow reaction 5h, then filtering reacting liquid, filtrate are poured into ice water while hot, are passed through
It is 7~8 that glacial acetic acid, which adjusts reaction solution pH, and it is multiple to be then extracted with ethyl acetate reaction solution, is merged after organic phase through anhydrous slufuric acid
4- methoxybenzene ethylidene methyl hydrazinocarboxylate 17.3g is concentrated to get after magnesium is dry;1H NMR(400MHz, DMSO-d6):δ
9.67 (s, 1H), 8.05 (d, J=4.0Hz, 1H), 7.69 (d, J=8.0Hz, 2H), 7.35 (d, J=8.0Hz, 2H), 3.76
(s,3H),3.42(s,3H),2.93(t,J1=8.0Hz, J2=8.0Hz, 2H), MS (ESI) m/z:223.8 (M+H+)。
Embodiment 2
In the more mouthfuls of reaction flasks with water segregator, the hydrazine hydrate 13g and dimethyl carbonate 9g that content is 80% are added
Toluene 200mL is to slowly warm up to flow back after mixing evenly, separates the moisture that reaction system has and generates by water segregator, leads to
Observation about back flow reaction 3h is crossed, moisture is not occurring in water segregator, is being cooled to room temperature, sodium methoxide is added into reaction system
Then under nitrogen protection 5.5g and 4- methoxybenzene acetaldehyde 15g is continuously heating to flow back, removed in time by water segregator anti-
The moisture that should be generated in the process, about back flow reaction 5h, TLC monitor the acetaldehyde fully reacting of 4- methoxybenzene, then filter while hot
Reaction solution, filtrate are poured into ice water, and adjusting reaction solution pH by glacial acetic acid is 7~8, and it is more that reaction solution is then extracted with ethyl acetate
It is secondary, 4- methoxybenzene ethylidene methyl hydrazinocarboxylate 19.6g is concentrated to get after anhydrous magnesium sulfate is dry after merging organic phase;1H NMR(400MHz,DMSO-d6): δ 9.67 (s, 1H), 8.05 (d, J=4.0Hz, 1H), 7.69 (d, J=8.0Hz, 2H),
7.35 (d, J=8.0Hz, 2H), 3.76 (s, 3H), 3.42 (s, 3H), 2.93 (t, J1=8.0Hz, J2=8.0Hz, 2H), MS
(ESI)m/z:223.8(M+H+)。
Embodiment 3
In the more mouthfuls of reaction flasks with water segregator, the hydrazine hydrate 13g and dimethyl carbonate 9g that content is 80% are added
Toluene 200mL is to slowly warm up to flow back after mixing evenly, separates the moisture that reaction system has and generates by water segregator, leads to
Observation about back flow reaction 3h is crossed, moisture is not occurring in water segregator, is being cooled to room temperature, sodium hydroxide is added into reaction system
Then under nitrogen protection 4g and 4- methoxybenzene acetaldehyde 15g is continuously heating to flow back, remove dereaction in time by water segregator
The moisture generated in the process, about back flow reaction 5h, then filtering reacting liquid, filtrate are poured into ice water while hot, pass through glacial acetic acid
Adjusting reaction solution pH is 7~8, and it is multiple to be then extracted with ethyl acetate reaction solution, is merged dry through anhydrous magnesium sulfate after organic phase
After be concentrated to get 4- methoxybenzene ethylidene methyl hydrazinocarboxylate 15.9g;1H NMR(400MHz,DMSO-d6): δ9.67(s,
1H), 8.05 (d, J=4.0Hz, 1H), 7.69 (d, J=8.0Hz, 2H), 7.35 (d, J=8.0Hz, 2H), 3.76 (s, 3H),
3.42(s,3H),2.93(t,J1=8.0Hz, J2=8.0Hz, 2H), MS (ESI) m/z:223.8 (M+H+)。
Embodiment 4
In more mouthfuls of reaction flasks, 4- methoxybenzene ethylidene methyl hydrazinocarboxylate 22g and 1,8- diazabicylo 11
Carbon -7- alkene 15g and elemental sulfur 6.5g adding into dichloromethane, after mixing evenly, under the conditions of 0 DEG C and under nitrogen protection,
Thionyl chloride 24g is added dropwise to reaction solution, after dripping, is slowly increased to room temperature, is stirred to react 1h at room temperature, pass through flowing
Reaction system gas generated is discharged in nitrogen, and control reaction temperature is in room temperature, after TLC monitors raw material fully reacting, to
Ice water 50mL is poured into reaction solution, 10min is stirred, separates organic phase, and water phase is extracted with dichloromethane repeatedly again, merges organic
Phase, then with active carbon decoloring, then after anhydrous magnesium sulfate is dry concentration through isolated methoxyphenyl -1 4- of silica gel column chromatography,
2-3- thiadiazoles 14.5g;1H NMR(400MHz,DMSO-d6): δ 8.41 (s, 1H), 7.62 (d, J=8.0Hz, 2H), 7.27
(d, J=8.0Hz, 2H), 3.71 (s, 3H), MS (ESI) m/z:193.5 (M+H+)。
Embodiment 5
In closed reactors, Salicylaldoxime 9g and acetic acid 30mL are added in dimethyl sulfoxide 200mL, are stirred
After uniformly, 4- methoxybenzene ethylidene methyl hydrazinocarboxylate 22g and potassium thiosulfate 19g are added, is removed in vacuum in reactor
Air, be passed through oxygen, the pressure in reactor made to reach 0.2MPa, be heated slowly to 120 DEG C, be stirred to react 4h, HPLC prison
The surplus of 4- methoxybenzene ethylidene methyl hydrazinocarboxylate in the reaction system is controlled less than 2%, room temperature is slowly dropped to, depressurizes whole
Except the complete acetic acid of unreacted, water 300mL is then added into reaction solution, it is then more with ethyl acetate 100mL extraction reaction solution
It is secondary, merge organic phase, then wash organic phase with sodium chloride solution, through the isolated 4- methoxybenzene of silica gel column chromatography after concentration
Base -1,2-3- thiadiazoles 17.7g;1H NMR(400MHz,DMSO-d6): δ 8.41 (s, 1H), 7.62 (d, J=8.0Hz, 2H),
7.27 (d, J=8.0Hz, 2H), 3.71 (s, 3H), MS (ESI) m/z:193.5 (M+H+)。
Embodiment 6
In closed reactors, Salicylaldoxime 18g and acetic acid 30mL are added in dimethyl sulfoxide 200mL, are stirred
After mixing uniformly, 4- methoxybenzene ethylidene methyl hydrazinocarboxylate 22g and potassium thiosulfate 19g (0.1mol) are added, vacuum is removed
Air in dereaction device, is passed through oxygen, and the pressure in reactor is made to reach 0.2MPa, is heated slowly to 120 DEG C, is stirred to react
4h is slowly dropped to room temperature, and the complete acetic acid of unreacted is divided exactly in decompression, and water 300mL is then added into reaction solution, then uses acetic acid second
Ester 100mL extraction reaction solution is multiple, merges organic phase, then wash organic phase with sodium chloride solution, through silica gel column chromatography after concentration
Isolated 4- methoxyphenyl -1,2-3- thiadiazoles 15.2g;1H NMR(400MHz,DMSO-d6):δ 8.41(s,1H),
7.62 (d, J=8.0Hz, 2H), 7.27 (d, J=8.0Hz, 2H), 3.71 (s, 3H), MS (ESI) m/z:193.5 (M+H+)
Embodiment 7
In closed reactors, Salicylaldoxime 9g and formic acid 30mL are added in dimethyl sulfoxide 200mL, are stirred
After uniformly, 4- methoxybenzene ethylidene methyl hydrazinocarboxylate 22g and potassium thiosulfate 19g are added, is removed in vacuum in reactor
Air, be passed through oxygen, the pressure in reactor made to reach 0.2MPa, be heated slowly to 120 DEG C, be stirred to react 4h, slowly drop
To room temperature, the complete formic acid of unreacted is divided exactly in decompression, and water 300mL is then added into reaction solution, is then extracted with ethyl acetate 100mL
It extracts reaction solution repeatedly, merges organic phase, then wash organic phase with sodium chloride solution, through the isolated 4- of silica gel column chromatography after concentration
Methoxyphenyl -1,2-3- thiadiazoles 12.8g;1H NMR(400MHz,DMSO-d6): δ 8.41 (s, 1H), 7.62 (d, J=
8.0Hz, 2H), 7.27 (d, J=8.0Hz, 2H), 3.71 (s, 3H), MS (ESI) m/z:193.5 (M+H+)。
Embodiment 8
In more mouthfuls of reaction flasks, under the conditions of -40 DEG C, under nitrogen protection, 4- methoxyphenyl -1,2-3- thiadiazoles
20g is added in anhydrous tetrahydro furan 150mL, and the tetrahydro dissolved with lithium methide 33g is slowly added dropwise after stirring evenly into reaction solution
Tetrahydrofuran solution 150mL stirs 1.5h under the conditions of -40 DEG C after dripping, and 1h is stirred to react being warming up to -20 DEG C, in the temperature
Under the conditions of be added dissolved with 3- chlorpromazine chloride 13g tetrahydrofuran solution 100mL, about 2h be added dropwise completely, be warming up to 0 after dripping
DEG C, continue to stir 30min, water 50min is then added into reaction solution, methylene chloride is added into reaction solution for quenching reaction
200mL separates organic phase after mixing evenly, who wants after being neutrality with dilute hydrochloric acid adjusting pH, then is extracted with dichloromethane repeatedly, closes
And organic phase, 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles is concentrated to get after being dried with anhydrous magnesium sulfate
23g;MS(ESI)m/z:283.9(M+H+);Elemental analysis calculated value [C12H11ClN2O2S]:C,50.97;H, 3.92;N,
9.91;Measured value: C, 50.65;H,3.99;N,9.84.
Embodiment 9
In more mouthfuls of reaction flasks, under the conditions of -40 DEG C, under nitrogen protection, 4- methoxyphenyl -1,2-3- thiadiazoles
20g is added in anhydrous tetrahydro furan 150mL, and four dissolved with n-BuLi 13g are slowly added dropwise after stirring evenly into reaction solution
Hydrogen tetrahydrofuran solution 150mL, stirs 1.5h under the conditions of -40 DEG C after dripping, and 1h is stirred to react being warming up to -20 DEG C, in the temperature
The tetrahydrofuran solution 100mL dissolved with 3- chlorpromazine chloride 13g is added under the conditions of degree, about 2h is added dropwise completely, heats up after dripping
To 0 DEG C, continues to stir 30min, water 50min is then added into reaction solution, methylene chloride is added into reaction solution for quenching reaction
200mL separates organic phase after mixing evenly, who wants after being neutrality with dilute hydrochloric acid adjusting pH, then is extracted with dichloromethane repeatedly, closes
And organic phase, 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles is concentrated to get after being dried with anhydrous magnesium sulfate
18.1g;MS(ESI)m/z:283.9(M+H+);Elemental analysis calculated value [C12H11ClN2O2S]:C,50.97;H, 3.92;N,
9.91;Measured value: C, 50.65;H,3.99;N,9.84
Embodiment 10
In more mouthfuls of reaction flasks, 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles 28g and 3,4- bis-
Aminoanisole 15g and triethylamine 10g is added in methylene chloride 300mL, stirs 30min at room temperature, is heated to 70 DEG C
It is stirred to react 50min, then to filtering reacting liquid, separates organic phase, water phase methylene chloride 30mL is extracted repeatedly, merged organic
Phase, then methylene chloride 200mL and Isosorbide-5-Nitrae-dioxane 200mL mixed solution is added after being concentrated after anhydrous magnesium sulfate is dry
In, add copper trifluoromethanesulfcomposite 3.6g and copper carbonate 2.5g after mixing evenly, reaction temperature rises to 80 DEG C, reacts cold after 3h
But to room temperature, water 50mL is added into reaction solution, then filtering reacting liquid, is evaporated off methylene chloride and 1 under vacuum conditions,
4- dioxane, then to be extracted with dichloromethane reaction solution multiple, merges organic phase, through silicon after being concentrated after anhydrous magnesium sulfate is dry
The isolated target compound 27.3g of plastic column chromatography;1H NMR(400MHz,DMSO-d6):9.03(s, 1H,NH-1H),7.74
(d, J=8.0Hz, 2H, Ar-2H), 7.04 (d, J=8.0Hz, 2H, Ar-2H), 6.88-6.69 (m, 3H) [" 6.85 (t, J1=
4.0Hz,J2=4.0Hz, 2H, Ar-2H), 6.71 (d, J=8.0Hz, 1H, Ar-1H) "], 3.84 (s, 3H, OCH3-3H),3.72
(d, J=4.0Hz, 6H, 2OCH3- 6H), 3.51 (d, J=4.0Hz, 2H, CH2-2H),2.72(t,J1=4.0Hz, J2=
4.0Hz,2H,CH2-2H);Elemental analysis calculated value [C20H21N3O4S]:C,60.13;H,5.30;N,10.52;Measured value: C,
60.47;H,5.25;N,10.39.
Embodiment 11
In more mouthfuls of reaction flasks, 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles 28g and 3,4- bis-
Aminoanisole 15g and triethylamine 10g is added in methylene chloride 300mL, stirs 30min at room temperature, is heated to 70 DEG C
It is stirred to react 50min, then to filtering reacting liquid, separates organic phase, water phase methylene chloride 30mL is extracted repeatedly, merged organic
Phase, then methylene chloride 200mL and Isosorbide-5-Nitrae-dioxane 200mL mixed solution is added after being concentrated after anhydrous magnesium sulfate is dry
In, six perchloric acid hydrate nickel 3.6g and copper carbonate 2.5g are added after mixing evenly, and reaction temperature rises to 80 DEG C, after reacting 3h
Be cooled to room temperature, be added water 50mL into reaction solution, then filtering reacting liquid, be evaporated off under vacuum conditions methylene chloride and
Isosorbide-5-Nitrae-dioxane, then to be extracted with dichloromethane reaction solution multiple, merges organic phase, concentration is through silicon after anhydrous magnesium sulfate is dry
The isolated target compound 22.9g of plastic column chromatography;1H NMR(400MHz,DMSO-d6):9.03(s,1H, NH-1H),7.74
(d, J=8.0Hz, 2H, Ar-2H), 7.04 (d, J=8.0Hz, 2H, Ar-2H), 6.88-6.69 (m, 3H) [" 6.85 (t, J1=
4.0Hz,J2=4.0Hz, 2H, Ar-2H), 6.71 (d, J=8.0Hz, 1H, Ar-1H) "], 3.84 (s, 3H, OCH3-3H), 3.72
(d, J=4.0Hz, 6H, 2OCH3- 6H), 3.51 (d, J=4.0Hz, 2H, CH2-2H),2.72(t,J1=4.0Hz, J2=
4.0Hz, 2H,CH2-2H);Elemental analysis calculated value [C20H21N3O4S]:C,60.13;H,5.30;N,10.52;Measured value: C,
60.47; H,5.25;N,10.39.
Embodiment 12
In more mouthfuls of reaction flasks, 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles 28g and 3,4- bis-
Aminoanisole 15g and triethylamine 10g is added in methylene chloride 300mL, stirs 30min at room temperature, is heated to 70 DEG C
It is stirred to react 50min, then to filtering reacting liquid, separates organic phase, water phase methylene chloride 30mL is extracted repeatedly, merged organic
Phase, then methylene chloride 200mL and Isosorbide-5-Nitrae-dioxane 200mL mixed solution is added after being concentrated after anhydrous magnesium sulfate is dry
In, magnesium perchlorate 2.5g and copper carbonate 2.5g are added after mixing evenly, and reaction temperature rises to 80 DEG C, is cooled to room after reacting 3h
Water 50mL is added into reaction solution for temperature, and then filtering reacting liquid, is evaporated off methylene chloride and Isosorbide-5-Nitrae-dioxy under vacuum conditions
Six rings, then to be extracted with dichloromethane reaction solution multiple, merges organic phase, is concentrated to get target chemical combination after anhydrous magnesium sulfate is dry
Object 35.2g;1H NMR(400MHz,DMSO-d6): 9.03 (s, 1H, NH-1H), 7.74 (d, J=8.0Hz, 2H, Ar-2H),
7.04 (d, J=8.0Hz, 2H, Ar-2H), 6.88-6.69 (m, 3H) [" 6.85 (t, J1=4.0Hz, J2=4.0Hz, 2H, Ar-
2H), 6.71 (d, J=8.0Hz, 1H, Ar-1H) "], 3.84 (s, 3H, OCH3- 3H), 3.72 (d, J=4.0Hz, 6H, 2OCH3-
6H), 3.51 (d, J=4.0Hz, 2H, CH2-2H),2.72(t,J1=4.0Hz, J2=4.0Hz, 2H, CH2-2H);Elemental analysis
Calculated value [C20H21N3O4S]:C,60.13;H,5.30;N,10.52;Measured value: C, 60.47;H, 5.25;N,10.39.
Embodiment 13
In more mouthfuls of reaction flasks, 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles 28g and 3,4- bis-
Aminoanisole 15g and triethylamine 10g is added in methylene chloride 300mL, stirs 30min at room temperature, is heated to 70 DEG C
It is stirred to react 50min, then to filtering reacting liquid, separates organic phase, water phase methylene chloride 30mL is extracted repeatedly, merged organic
Phase, then methylene chloride 200mL and Isosorbide-5-Nitrae-dioxane 200mL mixed solution is added after being concentrated after anhydrous magnesium sulfate is dry
In, six perchloric acid hydrate zinc 3.7g and copper carbonate 2.5g are added after mixing evenly, and reaction temperature rises to 80 DEG C, after reacting 3h
Be cooled to room temperature, be added water 50mL into reaction solution, then filtering reacting liquid, be evaporated off under vacuum conditions methylene chloride and
Isosorbide-5-Nitrae-dioxane, then to be extracted with dichloromethane reaction solution multiple, merges organic phase, is concentrated to get after anhydrous magnesium sulfate is dry
32.8g;1H NMR(400MHz,DMSO-d6): 9.03 (s, 1H, NH-1H), 7.74 (d, J=8.0Hz, 2H, Ar-2H), 7.04
(d, J=8.0Hz, 2H, Ar-2H), 6.88-6.69 (m, 3H) [" 6.85 (t, J1=4.0Hz, J2=4.0Hz, 2H, Ar-2H),
6.71 (d, J=8.0Hz, 1H, Ar-1H) "], 3.84 (s, 3H, OCH3- 3H), 3.72 (d, J=4.0Hz, 6H, 2OCH3-6H),
3.51 (d, J=4.0Hz, 2H, CH2-2H),2.72(t,J1=4.0Hz, J2=4.0Hz, 2H, CH2-2H);Elemental analysis calculates
It is worth [C20H21N3O4S]:C,60.13;H,5.30;N,10.52;Measured value: C, 60.47;H,5.25;N,10.39.
Embodiment 14
From CO2Liver cancer SMMC7721 Tissue Culture Flask is taken out in incubator, is proceeded as follows respectively: unscrewing bottle cap,
Culture solution carries out sterile working in waste liquid cylinder by alcolhol burner out, washes the culture solution in culture bottle twice with the PBS of 2mL, uses
0.25% trypsase is digested, and space between cells increase occurs in discovery to be seen, cell becomes termination when roundlet loop-shaped
Digestion makes cell detachment using liquid-transfering gun piping and druming culture bottle bottom, resulting cell suspending liquid is transferred in sterile centrifugation tube,
It is 800r/min, 3min that centrifuge, which is arranged, is centrifuged, and the supernatant in centrifuge tube is then slowly toppled over, and is added 2~5mL's
Culture solution carries out cell count under inverted microscope.According to count results, 5 are configured to corresponding culture solution ×
104Then the single cell suspension of cells/mL is inoculated in 96 orifice plates, and 100 μ L of every hole.96 orifice plates are put into 37 DEG C, 5%
CO2It is cultivated for 24 hours in incubator.
Target compound is formulated into required concentration: 0.16 μm of ol/L, 0.8 μm of ol/L, 4.0 μm of ol/L, 20.0 μm of ol/L,
100μmol/L.From CO296 orifice plates are taken out in incubator, the pastille culture medium of 100 μ L is added in every hole, and the drug of every kind of concentration is same
When set 3 multiple holes.As the hole of blank assay, isometric corresponding culture solution is added.Place it in 37 DEG C, 5%CO2Incubator
Middle culture 72h.The experiment uses docetaxel as positive control, each drug all use the cell of same batch difference algebra into
Row is tested three times.After 72 hours, under the conditions of being protected from light, the 20 μ L of MTT solution of 5mg/mL is added in every hole, continues to be put into CO2Culture
4h is cultivated in case, with liquid-transfering gun Aspirate supernatant, 150 μ L DMSO are added in every hole, and placing shaking table 5min is uniformly mixed it, are used
Microplate reader measures its absorbance OD value at 562nm wavelength, and cell proliferation inhibition rate calculation method is as follows: cell inhibitory effect
Rate=[ODControl-ODExperiment]/ODControl× 100%;Through detection target compound to the inhibiting rate IC of liver cancer SMMC772150It respectively reaches
4.73 μm of ol/L have certain inhibitory effect.
Embodiment 15
Target compound is formulated into required concentration: 0.16 μm of ol/L, 0.8 μm of ol/L, 4.0 μm of ol/L, 20.0 μm of ol/L,
100μmol/L.It is incubated for 5 minutes, is added later suitable jointly with the Wild type EGFR kinase solution of certain concentration at room temperature
Enzyme reaction substrate, ATP and the starting enzyme reaction process of amount, after 30 minutes, suitable reaction is added into enzyme reaction system eventually
Only liquid and detection liquid after being incubated for 1 hour, on porous plate enzyme mark colour developing instrument, measure the enzyme under specific compound various concentration
Vigor, and the inhibitory activity of the compounds on enzyme activities of various concentration is calculated, later according to quadruplex parameters, to various concentration
The inhibitory activity for closing enzyme activity under object is fitted, and calculate target compound is to the IC50 value of Wild type EGFR kinases
1.92μmol.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (8)
1. a kind of 1 with tyrosine-kinase enzyme inhibition activity, 2,3- thiadiazole drug molecules, it is characterised in that 1,2, the 3- thiophene
Diazoles drug molecular structure are as follows:
2. the preparation of the 1,2,3- thiadiazole drug molecule according to claim 1 with tyrosine-kinase enzyme inhibition activity
Method, it is characterised in that the specific preparation step of 1,2, the 3- thiadiazole drug molecule are as follows:
(1) 4- methoxybenzene acetaldehyde obtains 4- methoxybenzene ethylidene diazanyl first through condensation reaction with hydrazine hydrate and dimethyl carbonate
Sour methyl esters;
(2) 4- methoxybenzene ethylidene methyl hydrazinocarboxylate and sulphur reagent generation annulation obtain 4- methoxyphenyl -1,2-
3- thiadiazoles;
(3) 4- methoxyphenyl -1,2-3- thiadiazoles reacts to obtain 4- (4- first with 3- chlorpromazine chloride after organolithium reagent pulls out hydrogen
Phenyl) -5- chlroacetone base -1,2-3- thiadiazoles;
(4) substitution reaction occurs for 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles and 3,4- dimethoxyaniline
Target compound is obtained by the nucleophilic addition of imines under the action of catalyst afterwards.
3. the preparation of the 1,2,3- thiadiazole drug molecule according to claim 2 with tyrosine-kinase enzyme inhibition activity
Method, it is characterised in that: step (1) are as follows: in the more mouthfuls of reaction flasks with water segregator, the water for being 80% a certain amount of content
It closes hydrazine and toluene is added in dimethyl carbonate, be to slowly warm up to flow back after mixing evenly, reaction system is separated by water segregator and is had
And the moisture generated is cooled to room temperature, by there is not moisture in water segregator during observation back flow reaction to reaction system
It is middle a certain amount of alkali compounds to be added and then under nitrogen protection 4- methoxybenzene acetaldehyde is continuously heating to flow back, pass through
Water segregator removes the moisture generated in reaction process, and filtering reacting liquid, filtrate are poured into ice water while hot after reaction, pass through ice
It is 7~8 that acetic acid, which adjusts reaction solution pH, and it is multiple to be then extracted with ethyl acetate reaction solution, is merged after organic phase through anhydrous magnesium sulfate
4- methoxybenzene ethylidene methyl hydrazinocarboxylate is concentrated to get after drying;The 4- methoxybenzene acetaldehyde and hydrazine hydrate and carbonic acid
The inventory molar ratio of dimethyl ester is 1:2:1~1.2;The alkali compounds is anhydrous barium hydroxide, sodium hydroxide or first
Sodium alkoxide;The inventory molar ratio of the 4- methoxybenzene acetaldehyde and alkali compounds is 1:0.5~1.
4. the preparation of the 1,2,3- thiadiazole drug molecule according to claim 2 with tyrosine-kinase enzyme inhibition activity
Method, it is characterised in that: step (2) is using one of following two method:
A, in more mouthfuls of reaction flasks, a certain amount of 4- methoxybenzene ethylidene methyl hydrazinocarboxylate and 1,8- diazabicylo ten
One carbon -7- alkene and elemental sulfur adding into dichloromethane, after mixing evenly, under certain reaction temperature and under nitrogen protection, to
Thionyl chloride is added dropwise in reaction solution, after dripping, is slowly increased to room temperature, is stirred to react a period of time at room temperature, passes through stream
Reaction system gas generated is discharged in dynamic nitrogen, controls reaction temperature in room temperature, falls after reaction into reaction solution
Enter ice water, separate organic phase after mixing evenly, water tank is extracted with dichloromethane repeatedly again, merges organic phase, then through anhydrous slufuric acid
Concentration is through the isolated 4- methoxyphenyl -1,2-3- thiadiazoles of silica gel column chromatography after magnesium is dry;The reaction temperature is 0
℃;The 4- methoxybenzene ethylidene methyl hydrazinocarboxylate and 11 carbon -7- alkene of 1,8- diazabicylo and elemental sulfur and chlorine
The inventory molar ratio for changing sulfoxide is 1:1~1.1:2~2.1:2~2.1
B, in closed reactors, Salicylaldoxime and organic acid are added in dimethyl sulfoxide, after mixing evenly, then plus
Enter 4- methoxybenzene ethylidene methyl hydrazinocarboxylate and potassium thiosulfate, the air in reactor is removed in vacuum, is passed through oxygen, makes
Pressure in reactor reaches certain numerical value and is heated slowly to certain temperature again, is slowly dropped to room temperature after reaction, depressurizes whole
Except the complete organic acid of unreacted, a certain amount of water is then added into reaction solution, it is multiple to be then extracted with ethyl acetate reaction solution,
Merge organic phase, then washs organic phase with sodium chloride solution, through isolated methoxyphenyl -1 4- of silica gel column chromatography after concentration,
2-3- thiadiazoles;The inventory of 4- the methoxybenzene ethylidene methyl hydrazinocarboxylate and Salicylaldoxime and potassium thiosulfate
Molar ratio is 1:0.5:1;The organic acid is formic acid or acetic acid;The reaction pressure is 0.1~0.2MPa;Described is anti-
Answering temperature is 100~120 DEG C.
5. the preparation of the 1,2,3- thiadiazole drug molecule according to claim 2 with tyrosine-kinase enzyme inhibition activity
Method, it is characterised in that: step (3) are as follows: under -40 DEG C of conditions and nitrogen protection, a certain amount of 4- methoxyphenyl -1,2-
3- thiadiazoles is added in anhydrous tetrahydro furan, is slowly added dropwise into reaction solution after stirring evenly dissolved with a certain amount of organolithium reagent
Tetrahydrofuran solution, a period of time is stirred after dripping under the conditions of -40 DEG C, when being warming up to -20 DEG C and being stirred to react one section
Between, the tetrahydrofuran solution dissolved with 3- chlorpromazine chloride is added under the conditions of the temperature, 0 DEG C is warming up to after dripping, continues to stir
For a period of time, water quenching reaction is then added into reaction solution, methylene chloride is added into reaction solution, has separated after mixing evenly
Machine phase, who wants after being neutrality with dilute hydrochloric acid adjusting pH, then is extracted with dichloromethane repeatedly, merges organic phase, uses anhydrous magnesium sulfate
4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles is concentrated to get after drying;The organolithium reagent is methyl
Lithium or n-BuLi;The inventory of the 4- methoxyphenyl -1,2-3- thiadiazoles and organolithium reagent and 3- chlorpromazine chloride
Molar ratio is 1:1.5:1.
6. the preparation of the 1,2,3- thiadiazole drug molecule according to claim 2 with tyrosine-kinase enzyme inhibition activity
Method, it is characterised in that: step (4) are as follows: a certain amount of 4- (4- methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles
It is added in methylene chloride with 3,4- dimethoxyaniline and triethylamine, is heated to 70 DEG C of stirrings after mixing evenly at room temperature
Reaction a period of time, then to filtering reacting liquid, organic phase being separated, water phase is extracted with dichloromethane repeatedly, merge organic phase, then
It is added in methylene chloride and Isosorbide-5-Nitrae-dioxane mixed solution after being concentrated after anhydrous magnesium sulfate is dry, adds again after mixing evenly
Enter a certain amount of catalyst and catalysis adjuvant, reaction temperature rises to 80 DEG C, is cooled to room temperature after reaction, into reaction solution
Water is added, then filtering reacting liquid, is evaporated off methylene chloride and Isosorbide-5-Nitrae-dioxane, then use methylene chloride under vacuum conditions
It is multiple to extract reaction solution, merges organic phase, through the isolated targeted of silica gel column chromatography after being concentrated after anhydrous magnesium sulfate is dry
Close object;4- (4- the methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles and catalyst and catalysis adjuvant feed intake
Amount molar ratio is 1:0.1:0.2;4- (4- the methoxyphenyl) -5- chlroacetone base -1,2-3- thiadiazoles and 3,4- diformazan
The inventory molar ratio of oxygroup aniline and triethylamine is 1:1:1;The catalyst is copper trifluoromethanesulfcomposite, six perchloric acid hydrates
Nickel, magnesium perchlorate or six perchloric acid hydrate zinc;The catalysis adjuvant is copper carbonate.
7. application of the 1,2,3- thiadiazole drug molecule as described in claim 1 in anti-tumor activity.
8. 1,2,3- thiadiazole drug molecule as described in claim 1 is inhibiting the application in tyrosine kinase activity.
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